The exocrine pancreas consists of acinar cells that synthesize and secrete digestive enzymes, and duct cells that produce bicarbonate-rich fluid. Pancreatic malignancies may arise from either cell type. The molecular signals that lead to malignant transformation and subsequent growth advantage of these cells are not known. Recent studies indicate, however, that several cultured human pancreatic carcinoma cells have an overabundance of EGF receptors. The gene coding for the EGF receptor is a protooncogene that has been implicated in the process of tumor promotion. In the present proposal we plan to examine the molecular mechanisms that lead to an overabundance of EGF receptors in cultured human pancreatic carcinoma cells. Two approaches will be used. First, chromosomal analyses of seven distinct pancreatic cancer cells will be carried out in order to look for abnormalities in the region of chromosome 7 that is known to code for the human EGF receptor gene. Second, appropriate cDNA probes will be used to determine whether the cell lines that overexpress the EGF receptor exhibit an increased number of EGF receptor gene copies, or enhanced stability of its mRNA. The relevance of these observations to pancreatic cancer in humans will be evaluated by determining the frequency of overabundance of EGF receptors in biopsy specimen from pancreatic malignancies. A second important goal will be to study EGF receptor metabolism and phosphorylation in a pancreatic cancer cell line (Panc-I) that avidly binds and internalizes EGF without readily degrading the ligand.